International Journal of Molecular Sciences Review Acute Spinal Cord Injury: A Systematic Review Investigating miRNA Families Involved Enrica Pinchi 1, Alessandro Frati 2,3, Santina Cantatore 4, Stefano D’Errico 1,5, Raffaele La Russa 1,2, Aniello Maiese 1,2, Mauro Palmieri 3 , Alessandro Pesce 2,3, Rocco Valerio Viola 1 , Paola Frati 1,2 and Vittorio Fineschi 1,2,* 1 Department SAIMLAL, “Sapienza” University of Roma, 00161 Rome, Italy; [email protected] (E.P.); [email protected] (S.D.); raff[email protected] (R.L.R.); [email protected] (A.M.); [email protected] (R.V.V.); [email protected] (P.F.) 2 IRCCS “Neuromed” – Neurosurgery Division, 86077 Pozzilli (IS), Italy; [email protected] (A.F.); [email protected] (A.P.) 3 NESMOS Department – Neurosurgery Division, “Sapienza” University of Roma, 00189 Rome, Italy; [email protected] 4 Forensic Pathology Institute, University of Foggia, 71122 Foggia, Italy; [email protected] 5 Legal Medicine Division, Ospedale Sant’Andrea, 00189 Rome, Italy * Correspondence: vfi[email protected]; Tel.: +39-0649912722 Received: 13 March 2019; Accepted: 10 April 2019; Published: 13 April 2019 Abstract: Acute traumatic spinal cord injury (SCI) involves primary and secondary injury mechanisms. The primary mechanism is related to the initial traumatic damage caused by the damaging impact and this damage is irreversible. Secondary mechanisms, which begin as early as a few minutes after the initial trauma, include processes such as spinal cord ischemia, cellular excitotoxicity, ionic dysregulation, and free radical-mediated peroxidation. SCI is featured by different forms of injury, investigating the pathology and degree of clinical diagnosis and treatment strategies, the animal models that have allowed us to better understand this entity and, finally, the role of new diagnostic and prognostic tools such as miRNA could improve our ability to manage this pathological entity. Autopsy could benefit from improvements in miRNA research: the specificity and sensitivity of miRNAs could help physicians in determining the cause of death, besides the time of death. Keywords: acute spinal cord injury; pathophysiology; clinical management; postmortem techniques; animal models; miRNAs 1. Introduction Spinal cord injury (SCI) consists of a plethora of signs and symptoms resulting from a combination of different factors among which the primary impact, the subsequent cellular swelling, the continuous spinal cord compression, vascular (linked to the integrity of the arterial feeding and of the venous outflow), and intrinsic cellular mechanisms [1,2]. In recent years, there has been a progressive epidemiological increase and a trend reversal linked to a greater number of incidences in elderly people of a pathology historically linked to young age [3]. Acute traumatic SCI involves primary and secondary injury mechanisms. The primary mechanism is related to the initial traumatic damage caused by the damaging impact and this damage is irreversible. Secondary mechanisms, which begin as early as a few minutes after the initial trauma, include processes such as spinal cord ischemia, cellular excitotoxicity, ionic dysregulation, and free radical-mediated peroxidation [4,5]. Our paper is dedicated to provide a concise review in a rapidly evolving field—SCI—featured by different forms of injury, investigating the pathology and degree of clinical diagnosis and treatment Int. J. Mol. Sci. 2019, 20, 1841; doi:10.3390/ijms20081841 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2019, 20, 1841 2 of 26 Int. J. Mol. Sci. 2019, 20, 1841 2 of 28 strategies, the animals models that have allowed us to better understand this entity and, finally, the role oftreatment new diagnostic strategies, and the animals prognostic models tools that such have as allowed miRNA us to and better the understand perspectives this onentity the and, future of researchfinally, about the SCI role [ 6of]. new diagnostic and prognostic tools such as miRNA and the perspectives on the future of research about SCI [6]. 2. Functional and Neurological Implications of the Spinal Cord Injury 2. Functional and Neurological Implications of the Spinal Cord Injury 2.1. Traumatic SCI: Clinical Findings 2.1. Traumatic SCI: Clinical Findings SCI is generally identified in clinical settings because of its neurological consequences. Each SCI level, suchSCI as Cervicalis generally (CS), identified Thoracic in clinical (TS), and settings Lumbar because (LS) of spine its neurological SCI, has its consequences. typical presentations, Each SCI such level, such as Cervical (CS), Thoracic (TS), and Lumbar (LS) spine SCI, has its typical presentations, as a lesional and sublesional syndromes and motor and sensory clinical presentations, and possible such as a lesional and sublesional syndromes and motor and sensory clinical presentations, and concurrentpossible sphincter concurrent impairment sphincter impairment (Figure1). (Figure 1). FigureFigure 1. (A )1. Computed (A) Computed tomography tomography (CT) (CT) scan scan disclosingdisclosing a aThoracolumbar Thoracolumbar “C” “C”type typeSpine Spine Fracture Fracture DislocationDislocation (arrow), (arrow), with with (B) (B and) and (C ()C complete) complete SpinalSpinal Cord Cord Injury Injury (arrow). (arrow). (D) (3DD) reconstruction 3D reconstruction of of the CT scan disclosing the Spine Fracture Dislocation (arrow). the CT scan disclosing the Spine Fracture Dislocation (arrow). When the SCI regards the entire spinal cord, all the functions at the level and below of the lesion Whenare lost, the while SCI regardsif the damage the entire is incomplete, spinal cord, the co allnsequent the functions neurological at the presentations level and below depends of the on lesion are lost,the whilehorns, iftracts the damageand roots isinvolved. incomplete, In particular, the consequent in the typical neurological lesional syndrome, presentations damagedepends of the on the horns,posterior tracts horns and or roots dorsal involved. roots could In particular, cause hype inr- theor typicalhypoanalgesia, lesional while syndrome, flaccid damageparalysis, of the posteriormuscular horns hypotonia or dorsal and roots hypotrophy, could cause loss hyper- of reflexes, or hypoanalgesia, and fasciculations while appear flaccid in the paralysis, case of lesions muscular hypotoniaof the andanterior hypotrophy, horns or ventral loss ofroots. reflexes, and fasciculations appear in the case of lesions of the anterior hornsIn the or sublesional ventral roots. syndrome, the sensory clinical presentation is represented by loss of Inproprioception the sublesional and syndrome,pain, vibration, the touch, sensory and clinical temperature presentation sensations. is representedThe motor clinical by loss of presentation features spastic paralysis, hypertonia, and increased reflex response due to damage of proprioception and pain, vibration, touch, and temperature sensations. The motor clinical presentation the pyramidal tracts and of extrapyramidal controlling systems. features spastic paralysis, hypertonia, and increased reflex response due to damage of the pyramidal tracts and of extrapyramidal controlling systems. In the emergency scenario, nothing must be left to the eventuality and every patient suffering from SCI must undergo a standardized assessment, performed with dedicated evaluation tools, in order to receive an accurate prognostic information and a fine and complete neurological evaluation. Int. J. Mol. Sci. 2019, 20, 1841 3 of 26 2.2. Evaluating Tools Standardized tools have been created and subsequently validated in order to precisely assess and evaluate the neurological conditions of patients suffering from SCI [6]. The main advantages of such an approach include the possibility to uniform all the clinical observations in a similar fashion; to program and to obtain reliable results, both from trial concerning the clinical management; and the prognostic issues in SCI2. Each SCI patient admitted into an Emergency Department should currently undergo a standard evaluation [6,7]. Historically, the American Spinal Injury Association (ASIA) substituted, in the first half of the 1970s, the previous gold standard Frankel Evaluation Scale because of a more accurate neurological definition [8]. 2.2.1. Frankel Scale The Frankel Scale synthetizes the neurological conditions of the patient affected by SCI in a purely “functional” fashion, considering the residual sensory or motor functions below the injury level; the instrument classifies five groups of patients: (A) Patients with a full motor and full sensory deficit. (B) Patients with a full motor palsy but some residual sensory function level. (C) Residual motor function but not useful for an independent life. (D) Reduced strength in concern to the motor function which is besides useful. (E) Normal neurological function. It is noteworthy that in the original paper of 1969, concerning the B and C degrees, the integrity of the sensory function was considered to be collateral, and the effective functional breakpoint is the interval between C and D scores, by which the patients are considered or not considered to be independent [8]. 2.2.2. ASIA Scale In respect to the Frankel Scale, the ASIA score (and subsequent revised versions) overcomes the limitations concerning the simplified “below the injury level” concept. Furthermore, the sensory function evaluation is dermatomal-based, which means it is extremely accurate for each single dermatome. The anorectal sphincter